Huntington's disease (HD) is an autosomally inherited neurodegenerative disorder that is caused by expansion of CAG repeats in exon-1 of huntingtin (Htt). Enzymatic cleavage of mutant Htt protein leads to the generation of neurotoxic, amyloidogenic fragments and is one of the earliest events in HD pathogenesis. The environmental cues and the signaling pathways that regulate Htt cleavage are poorly understood, however. HD is an age-dependent disorder and age-related factors such as the accumulation of DNA damage and neuroinflammation are likely to influence its progression. The IkB kinase (IKK)/NF-kB signaling pathway is activated by these environmental factors and is implicated in the pathogenesis of HD. IKK? is responsive to DNA damage and mediates inflammatory responses. Our results demonstrate that pre- symptomatic HD mice have elevated IKK? activity localized to the striatum, while symptomatic HD mice also exhibit elevated IKK? activity in other brain regions including cortex. Inhibition of IKK? reduces the neurotoxicity of amyloidogenic fragments of Htt in a brain slice culture model of HD. We also find that IKK? activation induced by DNA damage promotes caspase-dependent WT and mutant Htt cleavage in post-mitotic human neurons. Genetic and chemical inhibition of IKK? prevents caspase activation and Htt cleavage, while increasing neuronal resiliency to DNA damage. Recent studies implicate IKK? in the phosphorylation of N-terminus (Ser13 and Ser16) of Htt. Phospho- mimetic modification of these residues ameliorates disease in HD mice. Preliminary studies from our laboratory and other investigators indicate that IKK? inhibition promotes the phosphorylation of Htt in neuronal models. Thus, IKK? is a key regulator of HD pathogenesis and its inhibition may be protective in HD. Moreover, deregulated IKK? is likely responsible for neuroinflammation, which occurs years before the onset of motor symptoms in patients. We propose to investigate the role of IKK? in HD pathogenesis in several animal models. We will delete IKK? in the brains of HD mice and examine whether the lack of IKK? prevents Htt cleavage, neuroinflammation and thereby ameliorates pathology. Furthermore, we plan to test the efficacy of small molecule inhibitors of IKK? as potentially novel therapeutics for HD.